Substituted steroidal isoxazoles



United States Patent 3,185,684 SUBSTITUTED STEROIDAL ISOXAZOLES Pietrode Ruggieri, Carmelo Gandolfi, and Umberto Guzzi, Milan, Italy,assignors to Ormonoterapia Richter S.p.A., a corporation of Italyv NoDrawing. Filed May 10, 1963, Ser. No. 279,630 Claims priority,application Italy, May 12, 1962,

9,51'2/ 62 Claims. (Cl. 260-43955) This invention relates to[3,2-c]-isoxazoles of androstane and of estrane substituted in the 5'position of the heterocyclic ring with an amino group, a halogen, or ahydroxy group, represented by the general formula wherein R and R aremembers selected from the group consisting of hydrogen and methyl, R isa member selected from the group consisting of halogen, aminoandhydroxy-groups, and X is a single or double bond.

To prepare these compounds, which are endowed with remarkable anabolicactivity, Zia-cyano-3-keto-androstanes and -estranes obtained by alkalitreatment of the corresponding [2,3-d1-isoxazoles (F. A. Zderic et al.,Chemistry and Industry, 1960, page 1625, and R. 0. Clinton et al.,Journal Organic Chemistry, 26, 279', 1961) were reacted withhydroxylamine to obtain 5'-amino-[3,2-c] -isoxazoles, which in turnyielded 5'-hydroxy-[3,2-c] -isoxazoles through acid hydrolysis, and the5'-halo-derivatives through diazotization and substitution.

The following examples are offered by way of illustration of thisinvention and are not to be construed as a limitation thereof.

EXAMPLE NO. 1

5 ot-androstane-l 76-01-[3,2-c]-5'-amin0-is0xaz0le A solution of 024part of hydroxylamine hydrochloride and 0.464 part of sodium acetatetrihydrate in 2 parts of water were added to a solution of 1 part ofZea-cyano- 5a-androstane-17fi-ol-3-one in 6 parts of ethanol. Afterrefluxing for 1 hour, the mixture was cooled and fully diluted, and theobtained product was recovered by filtration and recrystallized frommethanol. Yield: 097 part of5a-androstane-17fl-ol-[3,2-c]-5'-amino-isoxazole; M.P. 226228 C., and[a] =+49 (ethanol).

The following compounds were prepared by the same procedure from thecorresponding cyano ketones:

17a-methyl-5a-androstane-175-01-[3,2-c]-5'-amino isoxazole, M.P. 256 C.;[a] =+Z3 (chlorofrom); crystallization from methanol.

Androst-4-ene-17B-ol-[3,2-c]-5'-amino isoxazole, M.P.

145-i150 C.; [a] =+108 (chloroform), crystallization from ethyl ether.

SOL-65tl'3l16-17fi-Ol- [3 ,2-c] -5 '-amino-isoxazole, M.P. 243 C.; [a]=+95 (pyridine), crystallization from ethyl acetate.

EXAMPLE NO. 2

0.5 part of hydroxylamine hydrochloride was added to a solution of 1part of 2a-cyano-5a-androstane-17fl-ol- 3,135,584 '5 Patented May 25,195

3-one in 10 parts of pyridine. The mixture was allowed to standovernight at room temperature, diluted with water and filtered to give095 part of 2a-cyano-5u-androstane- 17/3-ol-3-one-3-oxime (M.P. 212 C.with decomposition; [a] =+60 (dioxane)), which were then refluxed for30' with 6 parts of pyridine. The mixture was then fully diluted, andthe product was collected by filtration and recrystallized frommethanol. Yield: 0.88 part ofSoc-androstane-17B-ol-[3,2-c]-5-amino-isoxazole; M.P. 226- 228 C.; [a]=+49 (ethanol).

EXAMPLE NO. 3

1 7 a-methyl-androst-4-ene- [3 ,2-c] -5 -amin0-isoxaz0le 0.25 part ofhydroxylamine hydrochloride was added to 0.5 part of17a-methyl-2a-cyano-androst-4-ene-175-01-3- one dissolved in 5 parts ofpyridine. The mixture was stored overnight at room temperature and thendiluted with water to give 0.48 part of17a-methyl-2a-cyano-androst-4-ene-l7 8-ol-3-one-3-oxime (M.P. 138-142C.; [a] =+172 (pyridine)), which were refluxed for 30 minutes with 5parts of pyridine. The mixture was concentrated and then diluted, andthe so-obtained product was recrystallized from methylenechloride-acetone. Yield: 0.38 part of17a-methyl-androst-4-ene-[3,2-c]-5'- amino-isoxazole; M.P. 223-225 C.,and [oc] =+89 (pyridine).

EXAMPLE NO. 4

Two parts of a 10.5% sodium nitrite solution were added with stirring,over a period of 1 hour, to a solution of 1 part of5a-androstane-l7B-ol-[3,2-c]-5-amino-isoxazole in parts of concentratedhydrochloric acid, the mixture being cooled throughout such addition toa temperature of -10 C. 0.2 part of copper powder was then added, andstirring was kept up for another 60 minutes, the temperature of thereacting mass being kept in the meanwhile at a temperature ranging from-8 to -3 C. The mixture was then neutralized with sodium hydroxide andextracted with ethyl acetate, and the extract was washed with ammoniaand water until neutral. The organic layer, by evaporation of thesolvent and subsequent recrystallization from acetone, yielded 0.42 partof 5a-androstane-17/i-ol-[3,2-c]-5'-chloro isoxazole; M.P. 208-210" C.,and [a] =53 (pyridine).

EXAMPLE NO. 5

5 a-androstan e-J 713-01-[3,2-c]-5'-br0m0-isoxaz0le 0.5 part of bromine,and subsequntly 6 parts of an 18% sodium nitrite solution were added toa solution of 1 g. of 5a-androstane-17/3-ol-[3,2-c]-5'-amino-isoxazolein parts of 48% hydrobromic acid, while cooling to about 5 C. At the endof 1 hour, the mixture was made alkaline with sodium hydroxide andextracted with ethyl acetate. The solvent was evaporated from theorganic phase and the product was chromatographed on alumina. Yield:0.25 part of 5a-androstane-l7fl-ol-[3,2-c]5'- bromo-isoxazole, havingM.P. 164 C.; and [oc] =+7l (chloroform) EXAMPLE NO. 6

5 ot-androstane-l 7,8-01- [3,2-0] -5'-hydroxy-isoxazole One part of5o-androstane-17}3-0l-[3,2-c]-5'-aminoisoxazole was refluxed for 20hours with 10 parts of ethanol and 10 parts of 20% (v./v.) sulfuricacid. After sodium hydroxide was added to neutrality, the mixture wasdiluted, and the product was collected by filtration and recrystallizedfrom ethanol. Yield: 0.85 part of Soc-androstane-173-ol-[3,2-c]-5'-hydroxy-isoxazole; M.P. 243- 245 C. (withdecomposition), and [u] =+46 (pyridine).

alcohol) 3 EXAMPLE N0. 7

1 7a-methyl-5a-andr0stane-1 7,8-01- [3,2-] -5'- 'hy d roxy -isoxaz0leOne part of 17a-methyl-5u-androstane-UB-ol-[3,2-01- 5-amino-isoxazoleWas refluxed for I20 hours with I parts of ethanol, 2 parts of water and7 parts of Amberlite IRC-120 (acid form). The mixture was filtered andthe filtrate concentrated: the solid product which was formed wasrecrystallized from ethanol. Yield: 0.57 part of17a-methyl-5a-androstane-175-01- [3,2-c] 5'-hydroxyisoxazole; M.P.265-268 C., and [a] =+48' (benzyl What we claim is:

1. A compound of the formula I0 References Cited by the Examiner UNITEDSTATES PATENTS 3,080,359 3/63 Ringold et al. 26039.5 3,100,771 8/63Manson 260239.5 15 3,145,200 8/ 64 Clinton et al. 260-23955 OTHERREFERENCES Finar: OrganieChernistry, vol. 1, p. 559, 3rd ed. (1959),Longrnans, Green & Co., New York. Marchetti et al.: Gazz. Chim. Stal.91, pp. 113341 LEWIS GOTTS, Primary Examiner.

1. A COMPOUND OF THE FORMULA